Pantoprazole Derivatives: Synthesis, Urease Inhibition Assay and In Silico Molecular Modeling Studies
Homa Azizian, Atefeh Esmailnejad, Vaezeh Fathi Vavsari, Shabnam Mahernia, Massoud Amanlou, Saeed Balalaie
Abstract
Abstract A number of pantoprazole derivatives were synthesized and screened for their urease inhibitory properties. Some of them showed potent inhibitions against jack bean urease. All compounds showed varying degree of IC 50 in the range of 25.85 to 181 μMol as compared to standard acetohydroxamic acid (AHA) (100±2.02 μMol). Derivatives bearing 5‐aryl‐1,3,4‐oxadiazole ring substitutions (aryl= pyrazyl, pyridyl and phenyl) were found to be more potent inhibitors than AHA and pantoprazole. The most promising compound, 2‐((3,4‐dimethoxypyridin‐2‐yl)methylthio)‐5‐(pyrazin‐2‐yl)‐1,3,4‐oxadiazole 12 , with IC 50 value of 25.85±1.21 showed remarkable urease inhibition activity. In silico molecular modeling investigation performed to rationalize the possible binding interaction and ADME properties of compounds over the active site of urease enzyme. The induced fit docking study showed that compound 12 interacted with conserved residues His593 and Arg609 located at the mouth of the urease active site flap and are essential for enzyme catalytic activity. These target compounds could be further studied as a lead skeleton for discovery of novel urease inhibitors.